DESCRIPTION (Investigator's Abstract): Alzheimer's disease is a major disorder aging, affecting the elderly population at accelerating rates above the age of 65. It is widely believed that the deposition a beta- amyloid protein in plaques during aging imitates the process of neurofibrillary degeneration in Alzheimer's disease. However, it has not been possible to produce an animal model of this process, as no animal species has previously been found that is capable of producing Alzheimer-type neurofibrillary tangles (NFTs). We recently discovered that NFT's composed of tau-immunoreactive paired helical filaments (PHF's) develop in cerebral neurons in the aging sheep. We would now like to exploit this new animal model of neurofibrillary degeneration to address some fundamental issues in the formation of NFT's. In the first study, we will extend our observations on the early deposition of PHFs at the branch points of dendrites to the electron microscopic level. These studies should elucidate the relationship of the abnormal tau proteins to the cytoskeleton of the degenerating neuron. In the second study, we will clone the genes for tau in sheep and rhesus monkeys. We will then compare the primary sequence of tau in sheep and human, two species that from PHF's to rat and monkey, which is not, to determine candidates for a sequence homology that can account for this molecular behavior. In the third set of studies, we will express recombinant sheep and monkey taus to examine the molecular basis for their differential susceptibility to forming PHFs. Finally, we will inject beta-amyloid protein in to the cerebral cortex of sheep to determine whether we can trigger neurofibrillary degeneration, either locally or in neurons that provide afferents to the injected site. These studies should provide important new information on the mechanism of NFT formation in Alzheimer's disease.